When It Comes To Depression, Serotonin Isn't The Whole Story

When I was 17 years old, I got so depressed that what felt like an enormous black hole appeared in my chest. Everywhere I went, the black hole went, too.

So to address the black-hole issue, my parents took me to a psychiatrist at Johns Hopkins Hospital. She did an evaluation and then told me this story:

"The problem with you," she explained, "is that you have a chemical imbalance. It's biological, just like diabetes, but it's in your brain. This chemical in your brain called serotonin is too, too low. There's not enough of it, and that's what's causing the chemical imbalance. We need to give you medication to correct that."

Then she handed my mother a prescription for Prozac.

That was the late '80s, but this story of a chemical imbalance brought on by low serotonin has remained very popular.

"I don't know of any story that has supplanted it," says Alan Frazer, a researcher who studies how antidepressant medications work. He is also chairman of the pharmacology department at the University of Texas Health Science Center at San Antonio.

"It definitely continues to live — absolutely," agrees his colleague Pedro Delgado, the chair of the psychiatry department at UT. "If you go to your community doctor, you're likely to hear some version of that."

But for many scientists who research depression, this explanation is no longer satisfying.

"Chemical imbalance is sort of last-century thinking. It's much more complicated than that," says Dr. Joseph Coyle, a professor of neuroscience at Harvard Medical School. "It's really an outmoded way of thinking."

Coyle, who is also the editor of the journal Archives of General Psychiatry, says that though serotonin plays a role in depression, low serotonin is likely not the cause of depression. Scientific thinking has clearly shifted, he says.

Still, the story of serotonin remains. Why does it continue to have such a powerful grip on the popular imagination?

The Link

According to Frazer, to understand how the story of low serotonin came to dominate our understanding of what causes depression, you need to go back to the late '50s, to a psychiatric hospital in Switzerland.

That's where psychiatrist Roland Kuhn gave a newly developed drug to 10 patients who had been paralyzed by depression for years. Over the course of three weeks, he watched a near-miracle occur.

"There was this lightening of their mood," Frazer says. "They became more energized, more interested in things around them."

This was the birth of the very first antidepressants, called tricyclics. And with that birth came a question: How could these drugs possibly be working? Researchers had some ideas, but it really wasn't until the mid '60s, when the cause of Parkinson's disease was discovered, that a real narrative began to take shape.

It turned out that Parkinson's — a brain disorder — was caused by a deficiency of a chemical in the brain called dopamine. This discovery influenced the way scientists thought about depression.

"There is no doubt in my mind that the Parkinson's story had a strong impact on the way that people were thinking about depression," Frazer says. "It became easy to speculate that depression was due to a deficiency."

The question, of course, was what was deficient? Which chemical was too low? For decades researchers argued this question, but no one candidate took the lead. And then came Prozac.

Prozac's Pull

Almost as soon as it was introduced in 1987, the antidepressant Prozac, which selectively targets the chemical serotonin, became a blockbuster. "Prozac just blew everything else out of the water," Frazer says.

This had less to do with the efficacy of Prozac (it is not better at treating depression than tricyclics, the earlier generation of antidepressants) than with the fact that the drug had relatively few side effects.

"It was very free of side effects," says Pedro Delgado. "And so it began to be used very widely, and there was a lot of enthusiasm for it."

That understates the case. In a very short time, Prozac became wildly popular, and again, Prozac worked on just one chemical in the brain: serotonin.

And really, it is because of the popularity of Prozac that the low-serotonin story took hold, even though, Frazer argues, the scientific research has not borne that out.

"I don't think there's any convincing body of data that anybody has ever found that depression is associated to a significant extent with a loss of serotonin," he says.

Delgado also makes this argument. In the 1990s, he carried out a study that showed that if you take a normal person and deplete them of serotonin, they will not become depressed. He says he feels this demonstrates that low serotonin doesn't cause depression.

Coyle is less absolute in his dismissal of the evidence on serotonin. His take is that while low serotonin probably doesn't cause depression, some abnormality in the serotonin system clearly plays a role. But most researchers have moved on, he says, and are looking at more fundamental issues like identifying the genes that might put people at risk for developing depression.

"What's being looked at are processes that are much more fundamental than just serotonin levels," he says. "We need to move beyond serotonin, and I think the field is."

Serotonin Sticking Around

So why are so many people still talking about low serotonin causing depression?

Frazer says it's probably because it has had, and continues to have, important cultural uses. For one, he says, by initially framing the problem as a deficiency — something that needed to be returned to normal — patients felt more comfortable taking a drug.

"If there was this biological reason for them being depressed, some deficiency that the drug was correcting," Frazer says, then taking a drug was OK. "They had a chemical imbalance and the drug was correcting that imbalance." In fact, he says, the story enables many people to come out of the closet about being depressed, which he views as a good thing.

Still, there's no question that the story also has downsides. Describing the problem exclusively in biological terms has convinced many people to take antidepressants when other therapies — like talk therapy — can work just as well.

One critic I talked to said the serotonin story distracted researchers from looking for other causes of depression. But Delgado agrees with Frazer and says the story has some benefits. He points out that years of research have demonstrated that uncertainty itself can be harmful to people — which is why, he says, clear, simple explanations are so very important.

"When you feel that you understand it, a lot of the stress levels dramatically are reduced," he says. "So stress, hormones and a lot of biological factors change."

Unfortunately, the real story is complicated and, in a way, not all that reassuring. Researchers don't really know what causes depression. They're making progress, but they don't know. That's the real story.

It's not exactly a blockbuster.

Copyright 2013 NPR. To see more, visit http://www.npr.org/.

Transcript

DAVID GREENE, HOST:

This is MORNING EDITION from NPR News. I'm David Greene.

STEVE INSKEEP, HOST:

And I'm Steve Inskeep. Good morning.

Today in Your Health, we begin a series about depression. And we start with NPR's Alix Spiegel, who looks at an idea about what causes depression. This is a notion introduced years ago, one that remains popular, that depression is caused by a chemical imbalance in the brain.

ALIX SPIEGEL, BYLINE: When I was 17 years old, I got so depressed that what felt like an enormous black hole appeared in my chest. Everywhere I went, the black hole went too. So to address this black hole problem, my parents eventually took me to a psychiatrist at Johns Hopkins Hospital. She did an evaluation and then told me this story.

The problem with you, she explained, is that you have a chemical imbalance. It's biological, just like diabetes, but it's in your brain. This chemical in your brain called serotonin is too, too low. There's not enough of it, and that's what's causing the chemical imbalance. We need to give you medication to correct that. Then she handed my mother a prescription for Prozac.

Now, that was the late '80s, but this story about a chemical imbalance brought on by low serotonin has remained popular. For the last 20 years it's been told all kinds of places.

(SOUNDBITE OF AD)

UNIDENTIFIED MAN: You know when you feel the weight of sadness.

SPIEGEL: In this 2004 commercial for Zoloft, a drug similar to Prozac, an unhappy looking cartoon circle bumps along, frowning and sighing frequently. Apparently life as a cartoon circle is not what it used to be. Why?

(SOUNDBITE OF AD)

UNIDENTIFIED MAN: Depression may be related to an imbalance of natural chemicals between nerve cells in the brain. Prescription Zoloft works to correct this imbalance.

SPIEGEL: In 2012, you can find that basic message repeated on the popular website Ways and How, a how-to website filled with colorful videos which includes this explanation in one of its tutorials on how to combat mental disorders.

(SOUNDBITE OF VIDEO)

UNIDENTIFIED WOMAN #1: Studies have shown that low levels of serotonin can cause many problems, such as depression and anxiety. If not addressed properly, these effects can be dangerous.

SPIEGEL: And it's not just websites or drug commercials. This idea that depression is caused by a chemical imbalance in the brain brought on by a deficit of serotonin is repeated in news accounts and in doctors' offices. It is a very sturdy little narrative. But for many scientists who research depression, this explanation no longer satisfies. Here's Dr. Joseph Coyle, a professor of neuroscience at Harvard Medical School, who's also the editor of psychiatry's most prestigious journal, the General Archives of Psychiatry.

DR. JOSEPH COYLE: Chemical imbalance is sort of last-century thinking. It's much more complicated than that. And it's not the way we talk about it. It's really an outmoded way of thinking.

SPIEGEL: While serotonin clearly plays a role in depression, Coyle says, low serotonin is probably not the cause of depression. Scientific thinking, he says, has shifted. Still, the story remains.

ALAN FRAZER: I'm not sure I know of any sort of story that has supplanted it.

SPIEGEL: This is Dr. Alan Frazer, chair of the department of pharmacology at the University of Texas Health Science Center in San Antonio. Frazer researches how antidepressant medications work. And I asked him to give me a history of the serotonin story, because I wanted to understand its staying power.

Frazer says the first time anyone used a pill to treat depression was in the '50s, when a psychiatrist in Switzerland gave a newly developed drug to 10 patients who had been paralyzed by depression for years and over three weeks observed a distinct change in their behavior.

FRAZER: There was this lightening of their mood. They became more energized. They became more interested in things around them. They weren't as tearful, etcetera.

SPIEGEL: That was the birth of the very first antidepressants. And with that birth came a question.

FRAZER: How are they working to make people better?

SPIEGEL: Now, researchers had some ideas, but it wasn't until the '60s that a real narrative began to take shape. That was when researchers discovered the cause of Parkinson's disease. Turned out that Parkinson's, a brain disorder, was caused by a deficiency in this chemical in the brain called dopamine. So it became easy to think, well, maybe the same thing is happening with depression.

FRAZER: It became easy to speculate that perhaps depression was due to a deficiency.

SPIEGEL: The question, of course, was what chemical was too low. Which was it? For decades, researchers argued this question. Then, Frazer says, something happened.

(SOUNDBITE OF MUSIC)

SPIEGEL: You know where we're going with this inspirational music, right? Prozac.

SPIEGEL: Almost as soon as it was introduced in 1987, the antidepressant Prozac was a blockbuster. It's a drug that targets serotonin. And according to Frazer, Prozac changed the public's relationship to antidepressants. Every antidepressant before Prozac had serious side effects. But Prozac was easy to take.

FRAZER: It doesn't cause people to get dry mouth, to be incontinent, to possibly fall down because of hypotension.

SPIEGEL: And because it had so few side effects, Prozac became wildly popular. And remember, it worked on just one chemical in the brain...

FRAZER: It worked on serotonin.

SPIEGEL: And according to Frazer, it is because of the popularity of Prozac that the low-serotonin story really came to dominate our thinking about depression, even though, Frazer argues, the scientific evidence doesn't back that up.

FRAZER: I don't think there's any convincing body of data that anybody has ever found that depression is associated, to a significant extent, with a loss of serotonin.

SPIEGEL: Pedro Delgado from the University of Texas is another researcher who makes this argument. In the '80s, he did a study that showed that if you take a normal person and deplete them of serotonin, they will not become depressed.

PEDRO DELGADO: That was the first really strong evidence which suggested that in human beings low serotonin wasn't causing depression.

SPIEGEL: Joseph Coyle, the editor of the General Archives of Psychiatry, who you heard from earlier, is less dismissive of the evidence on serotonin. His take is that while low serotonin probably doesn't cause depression, some abnormality in the serotonin system clearly plays a role. But he says most researchers have moved on. They're looking at more fundamental issues, like indentifying the genes which might put people at risk for developing depression.

COYLE: What's being looked at is processes that are much more fundamental than simply thinking about serotonin levels. We need to move beyond serotonin, and I think the field is.

SPIEGEL: So why do many people still talk about low serotonin causing depression? Why does this story stick?

Alan Frazer says that that way of framing the problem has allowed patients to feel better about taking a drug.

FRAZER: Feel better about themselves, if there was this biological reason for them being depressed, some deficiency, and the drug was correcting it. They had a chemical imbalance and the drug was correcting that imbalance.

SPIEGEL: In fact, he feels the story enabled many people to come out of the closet about being depressed and still does.

FRAZER: It's like yeah, I have depression, but I have a chemical imbalance and you have hyperthyroidism and you have a chemical imbalance and my chemical imbalance just happens to affect my brain.

SPIEGEL: Still, there's no question that the story also has downsides. Though everyone agrees that depression is caused by biology, at least in part, describing the problem exclusively in biological terms convinced many people that antidepressants were the only answer when other therapies - like talk therapy - can work just as well.

But Pedro Delgado agrees with Frazer that the story has benefits. Delgado points out that years of research have demonstrated that uncertainty itself can be harmful to people. Which is why, he says, clear, simple explanations are so very important.

DELGADO: When you feel that you understand it, a lot of the stress levels dramatically are reduced. So stress hormones and a lot of biological factors change.

SPIEGEL: And the real story is complicated, and in a way, not all that reassuring. Researchers don't know what causes depression. They're making progress, but they really don't know. That's the real story. It's not a blockbuster.

Alix Spiegel, NPR News.

(SOUNDBITE OF MUSIC)

INSKEEP: And that's Your Health on this Monday morning. We'll hear more about depression next week. Problems with the current antidepressants and an experimental drug that has changed the lives of some people with depression.